A growing family of regulatory proteins that deliver signals between cells of the hematopoietic and immune systems has been identified. These regulatory molecules are known as cytokines. Many of the cytokines have been found to control the growth, development and biological activities of cells of the hematopoietic and immune systems. These regulatory molecules include all of the colony-stimulating factors (GM-CSF, G-CSF, M-CSF, and multi CSF or interleukin-3), the interleukins (IL-1 through IL-10), the interferons (alpha, beta and gamma), the tumor necrosis factors (alpha and beta), erythropoietin and leukemia inhibitory factor (LIF). These cytokines exhibit a wide range of biologic activities with target cells from bone marrow, peripheral blood, fetal liver, and other lymphoid or hematopoietic organs. See, e.g., G. Wong and S. Clark, Immunology Today, 9(5):137 (1988).
The biochemical and biological identification and characterization of certain cytokines was hampered by the small quantities of the naturally occurring factors available from natural sources, e.g., blood and urine. Many of the cytokines have recently been molecularly cloned, heterologously expressed and purified to homogeneity. [D. Metcalf, "The Molecular Biology and Functions of the Granulocyte-Macrophage Colony Stimulating Factors," Blood, 67(2):257-267 (1986).] Among these cytokines are gamma interferon, human and murine GM-CSF, human G-CSF, human CSF-1 and human and murine IL-3. Several of these purified factors have been found to demonstrate regulatory effects on the hematopoietic and immune systems in vivo, including GM-CSF, MIP, M-CSF, G-CSF, IL-3, IL-2, IL-1, IL-7, IL-6, LIF, TNF, gamma-interferon, and erythropoietin.
Recently a new murine T cell growth factor, designated P40, was reported by J. Van Snick et al, J. Exp. Med., 169: 363-368 (1989).
The generation of erythrocytes from bone marrow or peripheral blood progenitor cells is a complex process that is supported in culture by several different hematopoietic growth factors. Erythropoietin (Epo), the primary regulator of the levels of circulating erythrocytes in vivo is absolutely required in culture to support the final stages of erythroid development including hemoglobinization. The growth and development of earlier erythroid progenitors, known as erythroid burst forming units (BFU-E) can be supported by several different cytokines including interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and, at least in the mouse system, IL-4 [See, R. Donahue et al, Blood, 66:1479 (1985); C. Sieff et al, Science, 230:1171 (1985); Y. Yang et al, Cell, 47:3 (1986); S. Emerson et al, J. Clin. Invest., 82:1282 (1988); S. Emerson et al, Blood, 74:49 (1989); D. Rennick, Proc. Natl. Acad. Sci., 84:6889 (1987) [Rennick I]; D. Rennick, Blood, 73:1828 (1989) [Rennick II]]. However, each of these cytokines interacts with several different hematopoietic cell lineages and none of them is specific in supporting erythropoiesis.
There remains a need in the art for additional proteins purified from their natural sources or otherwise produced in purified form, which are capable of stimulating hematopoiesis, specifically erythroid development, or enhancing immune responsiveness and are suitable for pharmaceutical use.